Each year ~1.5 million American women between ages of 45 and 55 enter into the perimenopause. Yet to be discovered is the impact perimenopause has on key brain regions involved in cognition and known to be vulnerable to Alzheimer's disease (AD). Women have a higher lifetime risk of developing AD and represent more than 60% of the Alzheimer's disease population. The mission of our Perimenopause in Brain Aging and Alzheimer's Disease Program Project is to discover the biological transformations that occur in the brain during the perimenopausal transition that can result in phenotypes at risk for development of Alzheimer's pathology. We seek to identify the mechanisms by which these changes occur and to translate these discoveries to determine the optimal timing and strategies for preventing conversion to the perimenopausal at-AD-risk phenotype. To achieve our mission, we have developed a focused research center model with an integrated set of four Projects and three Cores. Projects 1, 2 and 3 are basic, mechanistic and preclinical translational science investigations of the perimenopausal brain utilizing our program developed rodent models of human perimenopause. Project 4 uses the results of Project 1, 2 and 3 to inform its ancillary association analysis of existing data and samples from the NIA-funded clinical trial Early versus Late Intervention Trial with Estrogen (ELITE) (R01AG-024154). To achieve our Program mission, each project has a unique but complementary research focus with all Aims of all projects and cores addressing Program wide aims. Innovative and integrative features of our Program include: bidirectional translational research;rodent models of human perimenopause transition;custom designed gene arrays that include GWAS identified AD risk factor genes and bioenergetic, inflammatory and AD system pathways, shared customized data and document management. Program-wide gene array and bioinformatic analyses across all projects. Discovery of at-AD-risk phenotypes and the underlying mechanisms of phenotype development could potentially lead to the early identification of those at greatest risk for developing AD and mechanistically inform interventions to prevent the disease. Program research addresses NIA Strategic Goals A and C. PUBLIC HEALTH RELEVANCE: The Perimenopause in Brain Aging and Alzheimer's Disease Program Project will determine how the brain changes during the perimenopausal transition and how these changes can lead to development of early risk factors for developing Alzheimer's disease. The goal of these studies is the early identification of those at greatest risk for developing AD and the window of opportunity for interventions to prevent Alzheimer's disease in those at greatest risk postmenopausal women. REVIEW OF INDIVUDUAL COMPONENTS CORE A: ADMINISTRATIVE CORE;Dr. Roberta Brinton, Core Leader (CL). DESCRIPTION (provided by applicant): The mission of our Perimenopause in Brain Aging and Alzheimer's Disease Program Project is to discover the biological transformations that occur in the brain during the perimenopausal transition which can result in phenotypes predictive of risk for development of Alzheimer's pathology. We seek to identify the mechanisms by which these changes occur, and translate these discoveries to determine the optimal timing and strategies for preventing conversion to the perimenopausal at-risk phenotype. Successful execution of our Perimenopausal Program Project Aims demands a high degree of coordination, intellectual synergy, collaboration and communication across and among all Projects and Cores. Administrative Core provides a structural organization to facilitate timely and efficient communication and integrative links among Projects and Cores. The Administrative Core (Core A) will ensure the success of the Perimenopause Program Project through effective leadership, the provision of data management and biostatistical resources, and the forging of partnerships to synergize efforts and maximize resources. Administrative Core specific aims are: (1) Specific Aim 1: Lead and administer Perimenopause in Brain Aging and Alzheimer's Disease Program Project (manage and steward intellectual, technological and financial resources, identify and overcome barriers to progress, create liaisons with similarity-focused research and training programs);(2) Specific Aim 2: Provide organizational systems for data management and communication within the Program Project Members and External Reviewers (implement and maintain a Web-based data entry, data management, and animal- and specimen tracking system);(3) Specific Aim 3: Conduct program-wide integrated statistical and bioinformatic analysis (provide biostatistical consulting in the design, coordination, and analyses of projects, oversee gene array and bioinformatics data management on program data management system, integrate gene expression profile across program;conduct program-wide bioinformatics network analysis). PUBLIC HEALTH RELEVANCE: The Administrative Core (Core A) provides the organization to facilitate timely and efficient communication and integrative links among Projects and Cores. The Administrative Core will ensure the success of the Program Project through effective leadership, provision of data management and biostatistical and bioinformatics resources, and forging partnerships to synergize efforts and maximize resources.